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We have seen two patients whose hepatitis was due to the administration of aprindine, a new antiarrhythmic agent. In both patients evidence of hepatitis appeared within 3 weeks of initiating aprindine therapy and resolved rapidly when the drug was withdrawn. The reintroduction of aprindine in one patient was associated with the reappearance of hepatitis, which resolved despite continued administration of the drug.
A 48 year old man with severe coronary artery disease died approximately 33 hours after swallowing unknown amounts of aprindine, digoxin, furosemide, acenocoumarol, flurazepam, nitrazepam and lorazepam. Blood analysis carried out 40 min. before death showed no hydric or ionic imbalance; blood gases were normal. Serum digoxin concentration was 3.9 ng/ml; plasma concentration of aprindine was 2.5 mug/ml and plasma concentration of desethylaprindine was 386 ng/ml. Patient was profoundly comatose, hypotensive, and the electrocardiogram showed broad and bizarre QRS complexes; patient ultimately died in irreversible secondary ventricular fibrillation and asystole. Aprindine probably played a decisive role in the fatal outcome of this complex drug intoxication.
OBJECTIVES: The relationship between the efficacy of the anticholinergic action of disopyramide, cibenzoline and aprindine and age was examined in patients with paroxysmal and persistent atrial fibrillation. METHODS: This prospective, randomized study included 278 patients (200 men, 78 women, mean age 61 +/- 11 years) divided into two groups; the non-elderly group (age below 60 years) and the elderly group (age over 60 years). Successful termination was defined as conversion of sinus rhythm within 30 min of intravenous administration of 50 mg disopyramide (n = 91), 70 mg cibenzoline (n = 93) or 100 mg aprindine (n = 94) in this prospective and randomized study. RESULTS: No statistically significant difference was found in patient characteristics between the three agents. 1) The rate of conversion to sinus rhythm after disopyramide administration in the non-elderly group(37.8%) was significantly higher than that in the elderly group (17.4%, p = 0.0361). 2) The rate of conversion to sinus rhythm after cibenzoline administration in the non-elderly group (62.2%) tended to be greater than that in the elderly group (43.8%, p = 0.0972). 3) The rate of conversion to sinus rhythm after aprindine administration in the non-elderly group (25.6%) was not significantly higher than that in the elderly group (18.2%, p = 0.4474). CONCLUSIONS: The anticholinergic action of antiarrhythmic agents has an effect on successful termination in non-elderly patients with paroxysmal and persistent atrial fibrillation.
Clinical use of aprindine hydrochloride is occasionally complicated by agranulocytosis. The mechanisms that underlie this disorder are not well understood. Agranulocytosis developed in a 76-year-old woman one month after treatment with aprindine was begun. Her bone marrow was infiltrated with confluent lymphocyte and plasma cell nodules. Although her serum showed no leukoagglutinins, it was found to kill her own leukocytes in the presence of complement, as shown by suppression of postphagocytosis respiratory burst. When complement was omitted or when her serum was treated with anti-IgM, the cytotoxicity was partially suppressed. Treatment of serum with anti-IgG had no such effect. Cytotoxicity disappeared in 28 days, concomitant with return of polymorphonuclear neutrophil leukocytes. These findings offer evidence that aprindine neither potentiated nor suppressed cytotoxicity. Therefore, this drug is believed to stimulate development of an immunogenic clone that produces antileukocyte antibodies.
The effects of long-term aprindine administration on cardiac function were clinically investigated in seven patients with supraventricular or ventricular arrhythmias associated with organic heart disease. Three patients had normal cardiac function and four had various degrees of cardiac dysfunction before treatment with aprindine. The drug was administered orally in doses of 25 to 75 mg daily (mean +/- SD, 54 +/- 14 mg/day). The duration of follow-up ranged from six to 23 months (mean +/- SD, 14 +/- 6 months). An antiarrhythmic effect was achieved in five cases. No worsening or newly acquired symptoms or signs of cardiac dysfunction were recognized. No significant changes in end-diastolic dimension or ejection fraction were observed echocardiographically. Results of this study suggest that aprindine, which has been reported to have a negative inotropic action, does not cause significant deterioration of cardiac function even when given as long-term antiarrhythmic therapy to patients with cardiac dysfunction.
Aprindine hydrochloride is an antiarrhythmic agent presently undergoing clinical trials in the United States. Because of the narrow therapeutic-toxic ratio observed for aprindine, the long-term follow-up of these patients is important in determining the potential clinical effectiveness of this drug. In this report we examine our experience with 30 patients with drug-resistant arrhythmias who were discharged receiving aprindine and who were followed up for a mean period of 25 months.
Cardiac effects of aprindine, a relatively new antiarrhythmic agent, were investigated by means of echocardiography in nine patients with ventricular arrhythmias. Three patients had normal cardiac function, and six patients had dilated cardiomyopathy. Aprindine was administered orally in a dosage of 50 to 75 mg/d. The plasma concentrations were 0.86 +/- 0.12 micrograms/ml. No worsening of cardiac signs and symptoms was noted within four weeks. An antiarrhythmic effect was noted in six of the nine patients. Significant changes in end-diastolic dimension or ejection fraction were not observed. Changes in contractile state were also assessed using the peak systolic blood pressure-end-systolic dimension relationship in three patients; none of them showed a decrease in cardiac contractility. This study suggests that aprindine, in a dose sufficient to suppress arrhythmias, does not make cardiac function deteriorate, as evaluated echocardiographically, even in patients with cardiac dysfunction.
Aprindine hydrochloride was administered IV and orally to 20 dogs with ventricular tachycardia. Seventeen of the 20 dogs had been unsuccessfully treated with conventional antiarrhythmic drugs. Fifteen of the 20 dogs converted to sinus rhythm after IV aprindine therapy, 4 dogs demonstrated marked slowing of their ventricular tachycardia, and 1 dog showed an increase in the rate of ventricular tachycardia. Emesis, ataxia, salivation, and nystamus were observed in 7 dogs after IV aprindine therapy. One dog developed clinical and laboratory evidence compatible with acute hepatitis.
A procedure for the determinations of aprindine in human plasma was developed. After the addition of N,N-diethyl-N'-(1,2,3,4-tetrahydro-2-naphthyl)-N'-phenyl-1,3-propanediamine as an internal standard, the plasma was buffered to pH 8.0, and the drug and the internal standard were extracted into ethyl acetate-hexane (9:1 v/v). The compounds then were extracted from the organic phase into 0.02 N HCl. The acidic solution was made basic with 0.2 M tribasic sodium phosphate, and aprindine and the internal standard were extracted into a small volume of hexane. The compounds were analyzed by GLC using a nitrogen--phosphorus flame-ionization detector. The drug concentration and instrument response were linear for 0.10--1.00 microgram of aprindine/ml, the slope was 1.1416 (0.0141), the y intercept was 0.0096 +/- 0.0082, and the correlation coefficient was 0.99960 +/- 0.00002. The sensitivity of the method was 0.02 microgram of aprindine/ml. The within-day coefficient of variation was 9.50, 3.14, and 2.21% for 0.05, 0.20, 0.40, and 0.80 microgram of aprindine/ml, respectively. The between-day coefficient of variation was 17.4, 3.40, 2.07, and 1.54% at the same concentrations. Total precision values of 19.9, 4.60, 4.26, and 2.69% were obtained. The overall relative error of the method +1.33, +2.00, -0.07, and +0.25% at these concentrations.
A young woman with mitral valve prolapse and ventricular tachycardia refractory to numerous antiarrhythmics, received a trial of aprindine. During the course of treatment she developed a severe psychotic reaction that resolved after the drug was stopped. Her psychosis was unassociated with the other dose-related neurological side effects of aprindine, and occurred at borderline therapeutic levels of the drug.
Two patients are described who had atrioventricular nodal reentrant tachycardia (AVNRT) with 1:1 relationship in the control state, but in whom a varying degree of VA block during AVNRT was observed during therapy with aprindine. Aprindine, however, did not cause anterograde blockade of conduction over the slow AV nodal pathway during tachycardia. These observations support the conclusion that the bulk of atrial muscle is not a requisite part of the tachycardia circuit in AVNRT and that antiarrhythmic drugs may have disparate effects on conduction in the retrograde and anterograde limbs of the circuit.
A rapid and highly sensitive method for the determination in serum of aprindine, an antiarrhythmic drug, was developed employing gas chromatography with a surface ionization detector. No interfering peak from endogenous substances appeared when an organic phase was directly injected into the system after single extraction from a serum sample. A standard curve obtained was linear up to the serum level of 6 micrograms/ml, and the limit of sensitivity was 16 pg. The method described is applicable to routine therapeutic monitoring of serum concentrations of aprindine.
Viral-hepatitis-like hepatic damage ("aprindin hepatitis") developed in a 50-year-old woman after taking aprindin, the cause of the jaundice being confirmed by the same signs occurring when the drug was taken again after initial withdrawal.
A simulation model was developed to predict complex interaction between antiarrhythmic drugs and cardiac sodium channels. This model has four assumptions: (1) Vmax of the action potential is a linear indicator of available sodium channel conductance; (2) antiarrhythmic drugs block the channel by binding to a single common receptor site associated with the channel; (3) binding and dissociation rate constants differ for the three channel states: activated, inactivated and resting, and (4) both drug-free and drug-bound channels change states far more rapidly than binding and dissociation processes. Binding and dissociation rate constants for the three channel states were calculated from single cell experiments using guinea pig hearts. Vmax changes reflecting tonic and use-dependent sodium channel block in the presence of mexiletine and aprindine were simulated and compared with those obtained in the single cell experiments. The model predicted that 'tonic' Vmax inhibition would be enhanced, whereas 'use-dependent' ones would be attenuated after admixture of mexiletine with aprindine. The mechanisms would involve competitive interaction at the common receptor site. Single-cell experiments supported this prediction. We conclude that our simple two-drug binding model provides a useful tool to predict pharmacological interaction between class I antiarrhythmic drugs given in combination.
Electrocardiogram in a 15-year-old girl showed persistent supraventricular tachycardia at rates of 130 to 140 bpm. Electrophysiological study confirmed left atrial automatic tachycardia, which was transferred to sinus rhythm by intravenous infusion of aprindine (100 mg/10 min). Therefore, aprindine (60 mg/day) was administered orally, and neither recurrence of left atrial automatic tachycardia nor side effects were observed during subsequent follow-up period of 16 months.
Alterations of hemodynamics and contractility were studied in 6 patients in whom two consecutive runs of supraventricular tachycardias (SVT) were electrically induced. Following initiation there was an abrupt decrease of arterial blood pressure, left ventricular systolic pressure, dp/dtmax, cardiac index and stroke work index (SWI). These parameters -- with the exception of SWI -- increased in the course of the SVT, however, control values were not reached. Mean pulmonary artery pressure steadily increased and remained on an elevated level until the tachycardia was stopped. When the SVT was electrically terminated, there was a transient overshoot of mean arterial and left ventricular systolic pressure, while mean pulmonary artery pressure slowly returned to control values. When the tachycardia was stopped by i.v. infusion of N-)diethylamino-3-propyl)-N-phenyl-indanamine-2 (aprindin, Amidonal) -- started at the 7th minute -- there was no statistically significant difference, neither during the SVT nor after cessation as compared to the values of the first run. Only mean pulmonary artery pressure remained at a higher level after SVT was stopped. It may, therefore, be concluded that in patients with otherwise normal hearts aprindin applied in a dosage sufficient to stop the SVT, does not exhibit noteworthy inotropic side effects.
The effects of aprinidine (AC 1802), a new antiarrhythmic drug, were studied in 9 anesthetized pigs. Aprindine was administered intravenously in cumulative doses until serum levels larger than or equal to 8 mug/ml were obtained, which is more than three times the therapeutic level in man (+/- 2.5 mug/ml). Doses less than 1.75 mg/kg (serum levels 3.4 mug/ml) had no effect on the pump function of the heart, as preload, afterload, and the contractile state of the heart were not significantly altered. However, at these levels, electrocardiographic changes were significant as QRS increased to 132 +/- 14% of control (P less than 0.005). At the highest serum levels (8.7 mug/ml), cardiac output had decreased to 78 +/- 15% of control. This appears to be the result of negative inotropic properties of the drug, as preload remained unchanged and afterload actually decreased. Most striking at these levels were the electrocardiographic changes, as P-Q length increased to 281 +/- 93% of control and QRS width to 341 +/- 85%. The changes in the width of the QRS complex, prove to be the earliest indicator of aprindine activity and may serve as a warning of intoxication.
Aprindine hydrochloride is an antiarrhythmic drug now under investigation. The drug is most effective in prophylaxis of ventricular dysrhythmias. Previously recognized toxic effects include neurological side effects, nausea, vomiting, as well as a reported association with agranulocytosis. To our knowledge, this is the first report of agranulocytosis associated with documented elevated serum concentrations of aprindine. Further correlation of drug levels with toxic reactions may help in establishing the mechanism of bone marrow suppression.